Dosage forms and methods for enantiomerically enriched or pure bupropion

ABSTRACT

This disclosure relates to dosage forms containing an enantiomerically enriched or pure bupropion such as enantiomeric excess of (S)-bupropion, enantiomerically enriched (S)-bupropion, or enantiomerically pure (S)-bupropion and methods of using these dosage forms. These dosage forms may be administered to human beings in a reduced amount as compared to the amount of racemic bupropion that would be administered in the same situation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 16/579,305, filed Sep. 23, 2019; which is acontinuation-in-part of U.S. patent application Ser. No. 16/362,434,filed Mar. 22, 2019, which claims the benefit of U.S. provisional Pat.App. No. 62/734,021, filed Sep. 20, 2018; and 62/810,880, filed Feb. 26,2019, all of which are incorporated by reference herein in theirentirety.

BACKGROUND

Bupropion is approved for human use as a racemic mixture. It wasbelieved by many that bupropion and its metabolites rapidly racemize inthe human body.

SUMMARY

Described herein are dosage forms containing an enantiomeric excess of(S)-bupropion, enantiomerically enriched (S)-bupropion, orenantiomerically pure (S)-bupropion and methods of using those dosageforms. These dosage forms may be administered to human beings in areduced amount as compared to the amount of racemic bupropion that wouldbe administered in the same situation.

Some embodiments include a method of providing bupropion to the plasmaof a human being, comprising: selecting a human patient in need of apharmacokinetic profile provided by orally administering a referencedosage form containing a first amount of racemic bupropion at a firstdosing frequency; and orally administering a dosage form containing asecond amount of (S)-bupropion that is at least 95% enantiomericallypure at the first dosing frequency to achieve the same pharmacokineticprofile that would be achieved by administering the reference dosageform at the first dosing frequency; wherein the first dosing frequencyis once daily or twice daily; and wherein the second amount is about20-70%, about 40-60%, about 45-55%, or about 50% of the first amount.For example, if a particular pharmacokinetic profile is achievable byorally administering a dosage form containing 150 mg of racemicbupropion and the second amount is 40-60% of the first amount, thesecond amount is 60-90 mg. Thus, in this situation, 60-90 mg of(S)-bupropion would be administered once daily to achieve the samepharmacokinetic profile as would be achieved by administering 150 mg ofracemic bupropion once daily; or 60-90 mg of (S)-bupropion would beadministered twice daily to achieve the same pharmacokinetic profile aswould be achieved by administering 150 mg of racemic bupropion twicedaily.

For the purposes of this disclosure, if the dosage form containingenantiomerically pure (S)-bupropion is recognized by the FDA asbioequivalent to a dosage form containing racemic bupropion, then thetwo dosage forms have the same pharmacokinetic profile.

Some embodiments include a method of treating a condition that istreatable with racemic bupropion, comprising: selecting a human patienthaving the condition that is treatable by orally administering areference dosage form containing a first amount of racemic bupropion ata first dosing frequency; and orally administering a dosage formcontaining a second amount of (S)-bupropion that is at least 95%enantiomerically pure at the first dosing frequency to achieve the sametherapeutic effect that would be achieved by administering the referencedosage form at the first dosing frequency; wherein the first dosingfrequency is once daily or twice daily; and wherein the second amount isabout 20-70%, about 40-60%, about 45-55%, or about 50% of the firstamount. For example, if a condition is treatable by orally administeringa dosage form containing 150 mg of racemic bupropion and the secondamount is 40-60% of the first amount, the second amount is 60-90 mg.Thus, in this situation, 60-90 mg of (S)-bupropion would be administeredonce daily to treat a condition so that the same therapeutic effect isachieved as would be achieved by administering 150 mg of racemicbupropion once daily; or 60-90 mg of (S)-bupropion would be administeredtwice daily to treat a condition so that the same therapeutic effect isachieved as would be achieved by administering 150 mg of racemicbupropion twice daily.

DETAILED DESCRIPTION

The (S)-bupropion administered to the human being may beenantiomerically pure or enantiomerically enriched. For example, the(S)-bupropion may be at least 70%, at least 80%, at least 85%, at least90%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, at least 99.9%, or at least 99.99% enantiomerically pure, up to (ornearly) 100% enantiomerically pure. (S)-bupropion that is 99.99%enantiomerically pure contains 99.99% (S)-bupropion and 0.001%(R)-bupropion. For convenience, any of the above may be referred to as“(S)-bupropion.” This type of dosage form may be useful in treatingconditions where increased levels of (S)-bupropion and/or(R,R)-hydroxybupropion are therapeutically beneficial, or for treatinghuman beings in need of treatment with (S)-bupropion and/or(R,R)-hydroxybupropion.

It has been discovered that orally administering (S)-bupropion isbioequivalent or pharmacokinetically equivalent to administering abouttwice as much racemic bupropion. For example, a 75 mg dose of(S)-bupropion is bioequivalent to a dose of about 150 mg of racemicbupropion.

(S)-bupropion may be administered alone or in combination with anotherdrug. However, for some treatments, use of another drug may not bedesirable with (S)-bupropion or (R,R)-hydroxybupropion. For example,(S)-bupropion or (R,R)-hydroxybupropion may be the only compounds neededto treat the condition, additional drugs may not provide any significantbenefit, or adding additional drugs may unacceptably increase the riskof adverse events which outweigh any potential benefit that they mayprovide. Thus, some dosage forms are substantially free of any otherdrug, and some treatments involve administration of (S)-bupropionwithout co-administration of any other drug. For example, the dosageform may contain less than 10% by weight, less than 5% by weight, lessthan 2.5% by weight, less than 1% by weight, or less than 0.1% by weightof any other active pharmaceutical agent, as compared to the weight ofthe (S)-bupropion, or may contain no other drug.

The dosage forms and methods described above may be incorporated intomethods for treating a mammal, such as a human being, for providingtherapeutically effective plasma levels of (S)-bupropion or one of itsmetabolites, such as (R,R)-hydroxybupropion, erythrohydroxybupropion, orthreohydroxybupropion, or for otherwise providing desirable or enhancedplasma levels or pharmacokinetic properties of (S)-bupropion or one ofits metabolites.

For example, the dosage forms and methods may be used to treatneurological disorders, central nervous system disorders, psychiatricdisorders, neuropsychiatric disorders, or related conditions.

The term “treating” or “treatment” includes the diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals,or any activity that otherwise affects the structure or any function ofthe body of man or other animals.

Administration of (S)-bupropion, e.g. by oral administration, may occurone or more times in a single day, or one or more times a day formultiple days, such as multiple consecutive days. For example,(S)-bupropion may be administered once or twice daily for 1, 2, 3, 4, 5,6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41,42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90, or moreconsecutive days. The patient may be fasted prior to and/or after oraladministration of a dosage form containing (S)-bupropion.

In some embodiments, a treatment described above may includeadministering the dosage form containing (S)-bupropion, alone or incombination with other drug, once a day for 1, 2, 3, 4, 5, 6, 7, or moredays, followed by twice a day treatment. For example, the dosage formcontaining (S)-bupropion could be administered once a day on day 1, 2,and 3, and then twice a day starting on day 4, and continued twice a dayfor an extended period of time, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14,15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49,50-55, 56, 57-59, 32-59, 60, 61-89, 90, or more consecutive days, or forthe remainder of the treatment period.

Starting with a once daily dose for a short period of time, followed byincreasing the dose frequency to twice a day, may be helpful in reducingseizure risk, or in reducing the risk of other adverse events.

(S)-Bupropion has the structure shown below.

Unless otherwise indicated, any reference to a compound herein, such as(S)-bupropion, by structure, name, or any other means, includespharmaceutically acceptable salts; alternate solid forms, such aspolymorphs, crystals, solvates, hydrates, etc.; tautomers;isotopically-enriched compounds (e.g. deuterium enriched bupropion); orany chemical species that may rapidly convert to a compound describedherein under conditions in which the compounds are used as describedherein.

For dosage forms comprising (S)-bupropion, such as at least 95%, atleast 97%, at least 99%, or at least 99.9% enantiomerically purebupropion, any suitable amount of (S)-bupropion may be used. In someembodiments, a dosage form contains at least about 10 mg, at least about20 mg, at least about 30 mg, at least about 50 mg, at least about 60 mg,at least about 70 mg, at least about 80 mg, at least about 90 mg, atleast about 100 mg, about 1-50 mg, about 50-150 mg, about 50-100 mg,about 100-150 mg, 150-200 mg, about 100-200 mg, about 1-10 mg, about10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg,about 100-110 mg, about 100-120 mg, about 120-150 mg, about 1-30 mg,about 20-50 mg, about 50-80 mg, about 80-120 mg, about 100-150 mg, about150-180 mg, about 180-200 mg, about 70-95 mg, about 50-70 mg, about60-80 mg, about 60-90 mg, about 70-80 mg, about 70-74 mg, about 72-76mg, about 74-76 mg, about 74-78 mg, about 70-90 mg, about 30-60 mg,about 40-75 mg, about 50-90 mg, about 60-105 mg, about 60-120 mg, about70-120 mg, about 80-135 mg, about 80-150 mg, about 100-180 mg, about120-210 mg, about 140-240 mg, about 160-270 mg, about 70 mg, about 75mg, about 80 mg, about 100 mg of (S)-bupropion, or any amount in a rangebounded by any of these values. Ranges of amounts of (S)-Bu obtained bycombining any of the ranges or endpoints above are also contemplated,especially if the range obtained encompasses, or is near, one or morethe following values for the amount of (S)-bupropion in the dosage form:about 60 mg, about 75 mg, or about 90 mg. These are values that arebelieved to potentially be of particular utility. A dosage formcontaining an amount of (S)-bupropion listed above may be administeredonce, twice, or three times a day for a daily dose that is 1, 2, or 3times that of any dose amount or any dose range listed above, e.g. 2times 50-100 mg for a daily dose of 100-200 mg, or 3 times 50-100 mg fora daily dose of 150-300 mg. Any daily dose obtained by combining any ofthe dose ranges or endpoints above and multiplying that result by 1, 2,or 3 are also contemplated, especially if the range obtainedencompasses, or is near, one or more the following values: about 120 mg,about 150 mg, or about 180 mg. These are values that are believed topotentially be of somewhat more interest for average sized adults. Lowerdoses, such as about 1-50 mg or about 1-70 mg, given once or twice aday, may be somewhat more useful for the treatment of children. Higherdoses, e.g. over about 100 mg, given twice or three times a day, may besomewhat more useful for the treatment of larger adults.

The daily dose of (S)-bupropion may be intended to target specificpharmacokinetic parameters (such as a C_(max), an AUC, and/or anotherpharmacokinetic parameter of: bupropion, (S)-bupropion,hydroxybupropion, (R,R)-hydroxybupropion, (S,S)-hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or another metabolite ofracemic bupropion, or a combination thereof that result fromadministering a certain amount of racemic bupropion. For example, adaily dose of (S)-bupropion may be administered to target apharmacokinetic parameter that would result from a daily dose of about100-500 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg ofracemic bupropion. In order to achieve that pharmacokinetic parameter,for example, the amount of daily dose of (S)-bupropion administered maybe about 20-70%, about 40-60%, about 45-55%, or about 50% of the amountof the daily dose of racemic bupropion.

Because (S)-bupropion is unexpectedly the primary source of thebupropion and bupropion metabolites present in the blood, the amount of(S)-bupropion administered to a person can be considerably lower thanthe amount of racemic bupropion (or (R)-bupropion) that would beadministered to treat the same condition with the same effect. Forexample, if the amount of racemic bupropion administered to treat acondition is 150 mg, a lower amount of (S)-bupropion such as 5-50% or20-70% of that amount, i.e. 30-105 mg, can be administered to achieve asimilar effect. In some embodiments, the amount of (S)-bupropionadministered is selected to be about 5-70%, about 5-50%, about 20-70%,about 5-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%,about 50-60%, about 60-70%, about 20-50%, about 40-70%, about 40-60%,about 40-45%, or about 45-55%, of the amount of racemic bupropion thatwould be administered to treat the same human being for the samecondition

Some solid compositions may comprise at least about 5%, at least about10%, at least about 20%, at least about 50%, at least about 70%, atleast about 80%, about 10-30%, about 30-50%, about 50-80%, about 80-95%,about 10-50%, about 30-70%, or about 50-90% of (S)-bupropion by weight.

In some embodiments, the dosage form may be free, or substantially free,of any active pharmaceutical ingredients, or drugs, other than the(S)-bupropion. For example, the dosage form may contain less than 10% byweight, less than 5% by weight, less than 1% by weight, or less than0.1% by weight of any other active pharmaceutical ingredient, ascompared to the weight of the (S)-bupropion.

Administering (S)-bupropion may be useful in increasing plasma levels of(S)-bupropion by at least about 1.1-fold, at least about 1.2-fold, atleast about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold,at least about 1.6-fold, at least about 1.7-fold, at least about1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about2.5-fold, at least about 3-fold, at least about 4-fold, at least about5-fold, about 5-20 fold, at least about 10-fold, at least about 20-fold,at least about 50-fold, at least about 100-fold, at least about150-fold, at least about 200-fold, or more, about 10-15 fold, about10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about40-50 fold, about 50-60 fold, about 60-70 fold, about 70-80 fold, about80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold,about 120-130 fold, about 130-140 fold, about 140-150 fold, about150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190fold, or about 190-200 fold, as compared to the plasma level of(R)-bupropion obtained by administering a dosage form containing thesame amount of (R)-bupropion to the human being.

In some embodiments, the method is effective in increasing the AUC₀₋₁₂,such as the average AUC₀₋₁₂, the mean AUC₀₋₁₂, the median AUC₀₋₁₂, orthe AUC₀₋₁₂ of an individual, of (S)-bupropion by at least about1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at leastabout 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, atleast about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold,at least about 2-fold, at least about 2.5-fold, at least about 3-fold,at least about 4-fold, at least about 5-fold, at least about 8-fold, atleast about 10-fold, about 10-fold, at least about 15-fold, at leastabout 20-fold, at least about 25-fold, at least about 50-fold, at leastabout 100-fold, at least about 150-fold, at least about 200-fold, ormore, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 60-70fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about170-180 fold, about 180-190 fold, or about 190-200 fold, as compared tothe AUC₀₋₁₂ of (R)-bupropion obtained administering a dosage formcontaining the same amount of (R)-bupropion to the human being.

In some embodiments, the method achieves an AUC₀₋₁₂, such as the averageAUC₀₋₁₂, the mean AUC₀₋₁₂, the median AUC₀₋₁₂, or the AUC₀₋₁₂ of anindividual, of (S)-bupropion that is at least about 300 ng·hr/mL, atleast about 400 ng·hr/mL, at least about 500 ng·hr/mL, at least about600 ng·hr/mL, at least about 700 ng·hr/mL, at least about 750 ng·hr/mL,at least about 800 ng·hr/mL, at least about 850 ng·hr/mL, at least about900 ng·hr/mL, at least about 950 ng·hr/mL, at least about 1,000ng·hr/mL, at least about 1,100 ng·hr/mL, up to about 1,200 ng·hr/mL, upto about 1,300 ng·hr/mL, up to about 1,400 ng·hr/mL, up to about 1,500ng·hr/mL, up to about 1,600 ng·hr/mL, up to about 1,700 ng·hr/mL, up toabout 1,800 ng·hr/mL, about 300-400 ng·hr/mL, about 400-500 ng·hr/mL,about 500-600 ng·hr/mL, about 600-700 ng·hr/mL, about 700-800 ng·hr/mL,about 800-900 ng·hr/mL, about 900-1,000 ng·hr/mL, about 1,000-1,100ng·hr/mL, about 1,100-1,200 ng·hr/mL, about 1,200-1,300 ng·hr/mL, about1,300-1,400 ng·hr/mL, about 1,400-1,500 ng·hr/mL, about 1,500-1,600ng·hr/mL, about 1,600-1,700 ng·hr/mL, about 1,700-1,800 ng·hr/mL, about300-600 ng·hr/mL, about 600-900 ng·hr/mL, about 900-1,200 ng·hr/mL,about 1,200-1,500 ng·hr/mL, about 1,500-1,800 ng·hr/mL, about 300-800ng·hr/mL, about 800-1,300 ng·hr/mL, about 1,300-1,800 ng·hr/mL, or about300-1,800 ng·hr/mL. Ranges of AUC₀₋₁₂ obtained by combining any of theranges or endpoints above are also contemplated, especially if the rangeobtained encompasses, or is near, one or more the following values forAUC₀₋₁₂: 350 ng·hr/mL, 400 ng·hr/mL, 750 ng·hr/mL, or 900 ng·hr/mL.These are values that are believed to potentially be of particularutility.

In some embodiments, the method is effective in increasing the C_(max),such as the average C_(max), the mean C_(max), the median C_(max), orthe C_(max) of an individual, of (S)-bupropion by at least about1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at leastabout 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, atleast about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold,at least about 2-fold, at least about 2.5-fold, at least about 3-fold,at least about 4-fold, at least about 5-fold, at least about 8-fold,about 5-20 fold, at least about 10-fold, about 10-fold, at least about20-fold, at least about 25-fold, at least about 50-fold, at least about100-fold, at least about 150-fold, at least about 200-fold, or more,about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold,about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold,about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190fold, or about 190-200 fold, as compared to administering a dosage formcontaining the same amount of (R)-bupropion to the human being.

In some embodiments, the method achieves a C_(max), such as the averageC_(max), the mean C_(max), the median C_(max), or the C_(max) of anindividual, of (S)-bupropion that is at least about 30 ng/mL, at leastabout 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, atleast about 80 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL,at least about 100 ng/mL, at least about 105 ng/mL, at least about 110ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at leastabout 125 ng/mL, up to about 130 ng/mL, up to about 140 ng/mL, up toabout 150 ng/mL, up to about 160 ng/mL, up to about 170 ng/mL, up toabout 180 ng/mL, up to about 190 ng/mL, up to about 200 ng/mL, up toabout 210 ng/mL, up to about 220 ng/mL, about 30-40 ng/mL, about 40-50ng/mL, about 50-60 ng/mL, about 60-70 ng/mL, about 70-80 ng/mL, bout80-90 ng/mL, about 90-100 ng/mL, about 100-110 ng/mL, about 110-120ng/mL, about 120-130 ng/mL, about 130-140 ng/mL, about 140-150 ng/mL,about 150-160 ng/mL, about 160-170 ng/mL, about 170-180 ng/mL, about180-190 ng/mL, about 190-200 ng/mL, about 200-210 ng/mL, about 210-220ng/mL, about 50-70 ng/mL, about 70-90 ng/mL, about 30-60 ng/mL, about60-90 ng/mL, about 90-120 ng/mL, about 120-160 ng/mL, about 160-220ng/mL, about 30-90 ng/mL, about 90-150 ng/mL, about 150-220 ng/mL, about30-110 ng/mL, about 110-220 ng/mL, or about 30-220 ng/mL. Ranges ofC_(max) obtained by combining any of the ranges or endpoints above arealso contemplated, especially if the range obtained encompasses, or isnear, one or more the following values for C_(max): 45 ng/mL, 90 ng/mL,125 ng/mL, 150 ng/mL, or 180 ng/mL. These are values that are believedto potentially be of particular utility.

In some embodiments, the method is effective in increasing the C_(min),such as the average C_(min), the mean C_(min), the median C_(min), orthe C_(min) of an individual, of (S)-bupropion by at least about1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at leastabout 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, atleast about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold,at least about 2-fold, at least about 2.5-fold, at least about 3-fold,at least about 4-fold, at least about 5-fold, at least about 8-fold, atleast about 10-fold, at least about 20-fold, at least about 50-fold, atleast about 100-fold, at least about 150-fold, at least about 200-fold,or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold,about 110-120 fold, about 120-130 fold, about 130-140 fold, about140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180fold, about 180-190 fold, or about 190-200 fold, as compared toadministering a dosage form containing the same amount of (R)-bupropionto the human being.

In some embodiments, the method achieves a C_(min), such as the averageC_(min), the mean C_(min), the median C_(min), or the C_(min) of anindividual, of (S)-bupropion that is at least about 20 ng/mL, at leastabout 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, atleast about 40 ng/mL, about 20-60 ng/mL, about 20-25 ng/mL, about 25-30ng/mL, about 30-35 ng/mL, about 35-40 ng/mL, about 30-40 ng/mL, about40-45 ng/mL, about 45-50 ng/mL, about 30-50 ng/mL, about 40-50 ng/mL, orabout 50-60 ng/mL. Ranges of C_(min) obtained by combining any of theranges or endpoints above are also contemplated, especially if the rangeobtained encompasses, or is near, one or more the following values forC_(min): 20 ng/mL, 30 ng/mL, 40 ng/mL, or 50 ng/mL. These are valuesthat are believed to potentially be of particular utility.

Administering (S)-bupropion may be useful in increasing plasma levels of(R,R)-hydroxybupropion, by at least about 1.1-fold, at least about1.5-fold, at least about 2-fold, at least about 3-fold, at least about5-fold, at least about 10-fold, at least about 15-fold, at least about20-fold, at least about 40-fold, at least about 50-fold, at least about100-fold, at least about 150-fold, at least about 200-fold, or more,about 5-10 fold, about 5-25 fold, about 5-20 fold, about 20-30 fold,about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold,about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190fold, or about 190-200 fold, as compared to administering a dosage formcontaining the same amount of (R)-bupropion to the human being.

Administering (S)-bupropion may be useful in increasing the AUC₀₋₁₂,such as the average AUC₀₋₁₂, the mean AUC₀₋₁₂, the median AUC₀₋₁₂, orthe AUC₀₋₁₂ of an individual, of (R,R)-hydroxybupropion, by at leastabout 1.1-fold, at least about 1.5-fold, at least about 2-fold, at leastabout 3-fold, at least about 5-fold, about 6-fold, at least about10-fold, at least about 15-fold, at least about 20-fold, at least about40-fold, at least about 50-fold, at least about 100-fold, at least about150-fold, at least about 200-fold, or more, about 5-10 fold, about 5-25fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, ascompared to administering a dosage form containing the same amount of(R)-bupropion to the human being.

In some embodiments, the method achieves an AUC₀₋₁₂, such as the averageAUC₀₋₁₂, the mean AUC₀₋₁₂, the median AUC₀₋₁₂, or the AUC₀₋₁₂ of anindividual, of (R,R)-hydroxybupropion that is at least about 1,000ng·hr/mL, at least about 3,000 ng·hr/mL, at least about 4,000 ng·hr/mL,at least about 6,000 ng·hr/mL, at least about 7,000 ng·hr/mL, at leastabout 7,500 ng·hr/mL, at least about 8,000 ng·hr/mL, at least about8,500 ng·hr/mL, at least about 9,000 ng·hr/mL, at least about 9,500ng·hr/mL, at least about 10,000 ng·hr/mL, at least about 12,000ng·hr/mL, at least about 13,000 ng·hr/mL, about 4,000-6,000 ng·hr/mL,about 6,000-8,000 ng·hr/mL, about 8,000-10,000 ng·hr/mL, about10,000-12,000 ng·hr/mL, about 12,000-14,000 ng·hr/mL, about14,000-16,000 ng·hr/mL, about 16,000-18,000 ng·hr/mL, about18,000-20,000 ng·hr/mL, about 20,000-22,000 ng·hr/mL, about22,000-24,000 ng·hr/mL, about 4,000-10,000 ng·hr/mL, about 10,000-16,000ng·hr/mL, about 16,000-24,000 ng·hr/mL, about 4,000-24,000 ng·hr/mL, upto about 14,000 ng·hr/mL, up to about 16,000 ng·hr/mL, up to about18,000 ng·hr/mL, up to about 20,000 ng·hr/mL, up to about 22,000ng·hr/mL, up to about 24,000 ng·hr/mL, or up to about 30,000 ng·hr/mL.Ranges of AUC₀₋₁₂ obtained by combining any of the ranges or endpointsabove are also contemplated, especially if the range obtainedencompasses, or is near, one or more the following values for AUC₀₋₁₂:4,000 ng·hr/mL, 5,000 ng/mL, 10,000 ng·hr/mL, 16,000 ng·hr/mL, or 22,000ng·hr/mL. These are values that are believed to potentially be ofparticular utility.

Administering (S)-bupropion may be useful in increasing the C_(max),such as the average C_(max), the mean C_(max), the median C_(max), orthe C_(max) of an individual, of (R,R)-hydroxybupropion, by at leastabout 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, atleast about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold,at least about 1.7-fold, at least about 1.8-fold, at least about1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about3-fold, at least about 4-fold, at least about 5-fold, about 6-fold, atleast about 10-fold, at least about 20-fold, at least about 50-fold, atleast about 100-fold, at least about 150-fold, at least about 200-fold,or more, about 5-10 fold, about 10-20 fold, about 5-20 fold, about 20-30fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about180-190 fold, or about 190-200 fold, as compared to administering adosage form containing the same amount of (R)-bupropion to the humanbeing.

In some embodiments, the method achieves a C_(max), such as the averageC_(max), the mean C_(max), the median C_(max), or the C_(max) of anindividual, of (R,R)-hydroxybupropion that is at least about 150 ng/mL,at least about 200 at least about 300 ng/mL, at least about 400 ng/mL,at least about 500 ng/mL, at least about 600 ng/mL, at least about 700ng/mL, at least about 800 ng/mL, at least about 900 ng/mL, at leastabout 1,000 ng/mL, at least about 1,100 ng/mL, at least about 1,200ng/mL, at least about 1,300 ng/mL, up to about 1,400 ng/mL, up to about1,500 ng/mL, up to about 1,600 ng/mL, up to about 1,700 ng/mL, up toabout 1,800 ng/mL, up to about 1,900 ng/mL, up to about 2,000 ng/mL, upto about 2,100 ng/mL, up to about 2,200 ng/mL, up to about 2,300 ng/mL,about 300-400 ng/mL, about 400-500 ng/mL, about 500-600 ng/mL, about600-700 ng/mL, about 700-800 ng/mL, about 800-900 ng/mL, about 900-1,000ng/mL, about 1,000-1,100 ng/mL, about 1,100-1,200 ng/mL, about1,200-1,300 ng/mL, about 1,300-1,400 ng/mL, about 1,400-1,500 ng/mL,about 1,500-1,600 ng/mL, about 1,600-1,700 ng/mL, about 1,700-1,800ng/mL, about 1,800-1,900 ng/mL, about 1,900-2,000 ng/mL, about2,000-2,100 ng/mL, about 2,100-2,200 ng/mL, about 2,200-2,300 ng/mL,about 300-800 ng/mL, about 800-1,300 ng/mL, about 1,300-2,300 ng/mL, orabout 300-2,300 ng/mL. Ranges of C_(max) obtained by combining any ofthe ranges or endpoints above are also contemplated, especially if therange obtained encompasses, or is near, one or more of the followingvalues for C_(max): 400 ng/mL, 950 ng/mL, 1,500 ng/mL, or 2,100 ng/mL.These are values that are believed to potentially be of particularutility.

Administering (S)-bupropion may be useful in increasing the C_(min),such as the average the mean C_(min), the median C_(min), or the C_(min)of an individual, of (R,R)-hydroxybupropion, by at least about 1.1-fold,at least about 1.2-fold, at least about 1.3-fold, at least about1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at leastabout 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, atleast about 2-fold, at least about 2.5-fold, at least about 3-fold, atleast about 4-fold, at least about 5-fold, at least about 10-fold, atleast about 20-fold, at least about 50-fold, at least about 60-fold, atleast about 100-fold, at least about 150-fold, at least about 200-fold,or more, about 1-5 fold, about 5-10 fold, about 5-20 fold, about 20-30fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 60-70fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about170-180 fold, about 180-190 fold, or about 190-200 fold, as compared toadministering a dosage form containing the same amount of (R)-bupropionto the human being.

In some embodiments, the method achieves a C_(min), such as the averageC_(min), the mean the median C_(min), or the C_(min) of an individual,of (R,R)-hydroxybupropion that is at least about 150 ng/mL, at leastabout 200 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, atleast about 500 ng/mL, at least about 600 ng/mL, at least about 700ng/mL, at least about 800 ng/mL, at least about 900 ng/mL, at leastabout 1,000 ng/mL, at least about 1,100 ng/mL, at least about 1,200ng/mL, up to about 1,300 ng/mL, up to about 1,400 ng/mL, up to about1,500 ng/mL, up to about 1,600 ng/mL, up to about 1,700 ng/mL, up toabout 1,800 ng/mL, up to about 1,900 ng/mL, up to about 2,000 ng/mL, upto about 2,100 ng/mL, up to about 2,200 ng/mL, up to about 2,300 ng/mL,about 200-300 ng/mL, about 300-400 ng/mL, about 400-500 ng/mL, about500-600 ng/mL, about 600-700 ng/mL, about 700-800 ng/mL, about 800-900ng/mL, about 900-1,000 ng/mL, about 1,000-1,100 ng/mL, about 1,100-1,200ng/mL, about 1,200-1,300 ng/mL, about 1,300-1,400 ng/mL, about1,400-1,500 ng/mL, about 1,500-1,600 ng/mL, about 300-700 ng/mL, about700-1,100 ng/mL, or about 1,100-1,600 ng/mL. Ranges of C_(min) obtainedby combining any of the ranges or endpoints above are also contemplated,especially if the range obtained encompasses, or is near, one or more ofthe following values for C_(min): 350 ng/mL, 600 ng/mL, 700 ng/mL, 1,000ng/mL, or 1,400 ng/mL. These are values that are believed to potentiallybe of particular utility.

Administering (S)-bupropion to a human being may result in(R,R)-hydroxybupropion being at least 90%, 95%, 97%, 97.2%, 97.4%,97.6%, 97.8%, or 98% of the total of amount of (R,R)-hydroxybupropionand (S,S)-hydroxybupropion present in the plasma of the human being.

In some embodiments, the method achieves an AUC₀₋₁₂, such as the averageAUC₀₋₁₂, the mean AUC₀₋₁₂, the median AUC₀₋₁₂, or the AUC₀₋₁₂ of anindividual, of erythrohydroxybupropion that is at least about 500ng·hr/mL, at least about 600 ng·hr/mL, at least about 800 ng·hr/mL, atleast about 1,000 ng·hr/mL, at least about 1,200 ng·hr/mL, up to about1,400 ng·hr/mL, up to about 1,600 ng·hr/mL, up to about 1,800 ng·hr/mL,up to about 2,000 ng·hr/mL, up to about 2,200 ng·hr/mL, up to about2,400 ng·hr/mL, up to about 2,600 ng·hr/mL, up to about 2,800 ng·hr/mL,up to about 3,000 ng·hr/mL, about 500-600 ng·hr/mL, about 600-800ng·hr/mL, about 800-1,000 ng·hr/mL, about 1,000-1,200 ng·hr/mL, about1,200-1,400 ng·hr/mL, about 1,400-1,600 ng·hr/mL, about 1,600-1,800ng·hr/mL, about 1,800-2,000 ng·hr/mL, about 2,000-2,200 ng·hr/mL, about2,200-2,400 ng·hr/mL, about 2,400-2,600 ng·hr/mL, about 2,600-2,800ng·hr/mL, about 2,800-3,000 ng·hr/mL, about 500-1,000 ng·hr/mL, about1,000-1,500 ng·hr/mL, about 1,500-2,000 ng·hr/mL, about 2,000-2,500ng·hr/mL, about 2,500-3,000 ng·hr/mL, about 500-1,500 ng·hr/mL, about1,500-3,000 ng·hr/mL, about 2,000-3,000 ng·hr/mL, or about 500-3,000ng·hr/mL. Ranges of AUC₀₋₁₂ obtained by combining any of the ranges orendpoints above are also contemplated, especially if the range obtainedencompasses, or is near, one or more the following values for AUC₀₋₁₂:500 ng·hr/mL, 1,300 ng·hr/mL, 1,800 ng·hr/mL, or 2,600 ng·hr/mL. Theseare values that are believed to potentially be of particular utility.

In some embodiments, the method achieves a C_(max), such as the averageC_(max), the mean C_(max), the median C_(max), or the C_(max) of anindividual, of erythrohydroxybupropion that is at least about 40 ng/mL,at least about 60 ng/mL, at least about 80 ng/mL, at least about 90ng/mL, at least about 100 ng/mL, at least about 120 ng/mL, at leastabout 140 ng/mL, up to about 160 ng/mL, up to about 180 ng/mL, up toabout 200 ng/mL, up to about 220 ng/mL, up to about 240 ng/mL, up toabout 260 ng/mL, up to about 280 ng/mL, about 40-60 ng/mL, about 60-80ng/mL, about 80-100 ng/mL, about 100-120 ng/mL, about 120-140 ng/mL,about 140-160 ng/mL, about 160-180 ng/mL, about 180-200 ng/mL, about200-220 ng/mL, about 220-240 ng/mL, about 240-260 ng/mL, about 260-280ng/mL, about 280-300 ng/mL, about 40-100 ng/mL, about 100-150 ng/mL,about 150-200 ng/mL, about 200-250 ng/mL, about 250-280 ng/mL, about40-120 ng/mL, about 120-200 ng/mL, about 200-280 ng/mL, or about 40-280ng/mL. Ranges of C_(max) obtained by combining any of the ranges orendpoints above are also contemplated, especially if the range obtainedencompasses, or is near, one or more the following values for C_(max):60 ng/mL, 120 ng/mL, 200 ng/mL, or 240 ng/mL. These are the values thatare believed to potentially be of particular utility.

In some embodiments, the method achieves an AUC₀₋₁₂, such as the averageAUC₀₋₁₂, the mean AUC₀₋₁₂, the median AUC₀₋₁₂, or the AUC₀₋₁₂ of anindividual, of threohydroxybupropion that is at least about 2,000ng·hr/mL, at least about 3,000 ng·hr/mL, at least about 4,000 ng·hr/mL,at least about 5,000 ng·hr/mL, at least about 6,000 ng·hr/mL, at leastabout 7,000 ng·hr/mL, up to about 8,000 ng·hr/mL, up to about 9,000ng·hr/mL, up to about 10,000 ng·hr/mL, up to about 11,000 ng·hr/mL, upto about 12,000 ng·hr/mL, up to about 13,000 ng·hr/mL, up to about14,000 ng·hr/mL, up to about 15,000 ng·hr/mL, about 2,000-15,000ng·hr/mL, about 2,000-3,000 ng·hr/mL, about 3,000-4,000 ng·hr/mL, about4,000-5,000 ng·hr/mL, about 5,000-6,000 ng·hr/mL, about 6,000-7,000ng·hr/mL, about 7,000-8,000 ng·hr/mL, about 8,000-9,000 ng·hr/mL, about9,000-10,000 ng·hr/mL, about 10,000-11,000 ng·hr/mL, about 11,000-12,000ng·hr/mL, about 12,000-13,000 ng·hr/mL, about 13,000-14,000 ng·hr/mL,about 14,000-15,000 ng·hr/mL, about 2,000-6,000 ng·hr/mL, about6,000-10,000 ng·hr/mL, about 10,000-15,000 ng·hr/mL, about 2,000-9,000ng·hr/mL, or about 9,000-15,000 ng·hr/mL. Ranges of AUC₀₋₁₂ obtained bycombining any of the ranges or endpoints above are also contemplated,especially if the range obtained encompasses, or is near, one or morethe following values for AUC₀₋₁₂: 3,000 ng·hr/mL, 6,000 ng·hr/mL, 8,000ng·hr/mL, or 12,000 ng·hr/mL. These are the values that are believed topotentially be of particular utility.

In some embodiments, the method achieves a C_(max), such as the averageC_(max), the mean C_(max), the median C_(max), or the C_(max) of anindividual, of threohydroxybupropion that is at least about 200 ng/mL,at least about 300 ng/mL, at least about 400 ng/mL, at least about 450ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at leastabout 700 ng/mL, up to about 800 ng/mL, up to about 900 ng/mL, up toabout 1,000 ng/mL, up to about 1,100 ng/mL, up to about 1,200 ng/mL, upto about 1,300 ng/mL, up to about 1,400 ng/mL, about 200-300 ng/mL,about 300-400 ng/mL, about 400-500 ng/mL, about 500-600 ng/mL, about600-700 ng/mL, about 700-800 ng/mL, about 800-900 ng/mL, about 900-1000ng/mL, about 1,000-1,100 ng/mL, about 1,100-1,200 ng/mL, about1,200-1,300 ng/mL, about 1,300-1,400 ng/mL, about 200-500 ng/mL, about500-800 ng/mL, about 800-1,100 ng/mL, about 1,100-1,400 ng/mL, about200-800 ng/mL, about 800-1400 ng/mL, or about 200-1,400 ng/mL. Ranges ofC_(max) obtained by combining any of the ranges or endpoints above arealso contemplated, especially if the range obtained encompasses, or isnear, one or more the following values for C_(max): 300 ng/mL, 600ng/mL, 900 ng/mL, or 1,200 ng/mL. These are values that are believed topotentially be of particular utility.

Unless otherwise indicated, any reference to a compound herein, such as(S)-bupropion, by structure, name, or any other means, includespharmaceutically acceptable salts; alternate solid forms, such aspolymorphs, crystals, solvates, hydrates, etc.; tautomers;deuterium-modified compounds; or any chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

(S)-Bupropion, alone or in a combination with another drug may becombined with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice asdescribed, for example, in Remington's Pharmaceutical Sciences, 2005.The relative proportions of active ingredient and carrier may bedetermined, for example, by the solubility and chemical nature of thecompounds, chosen route of administration, and standard pharmaceuticalpractice.

(S)-bupropion drug may be administered to a human patient in a varietyof forms adapted to the chosen route of administration, e.g., orally orparenterally. Parenteral administration in this respect includesadministration by the following routes: intravenous, intramuscular,subcutaneous, intraocular, intrasynovial, transepithelial includingtransdermal; ophthalmic; sublingual; and buccal, and topically includingophthalmic; dermal; ocular; rectal; nasal; etc.

(S)-bupropion may be formulated for oral administration, for example,with an inert diluent or with an edible carrier, or it may be enclosedin hard or soft shell gelatin capsules, compressed into tablets, orincorporated directly with the food of the diet. For oral therapeuticadministration, the active compound may be incorporated with anexcipient and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules and the like containing (S)-bupropionmay also contain one or more of the following: a binder such as gumtragacanth, acacia, corn starch, or gelatin; an excipient, such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid, and the like; a lubricant such as magnesiumstearate; a sweetening agent such as sucrose, lactose, or saccharin; ora flavoring agent such as peppermint, oil of wintergreen, or cherryflavoring. When the dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier. Various othermaterials may be present as coating, for instance, tablets, pills, orcapsules may be coated with shellac, sugar or both. A syrup or elixirmay contain the active compound, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and flavoring, such as cherryor orange flavor. It may be desirable for material in a dosage form orpharmaceutical composition to be pharmaceutically pure and substantiallynon-toxic in the amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

(S)-bupropion may be formulated for parental or intraperitonealadministration. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant. A dispersion can also have an oil dispersedwithin, or dispersed in, glycerol, liquid polyethylene glycols, andmixtures thereof. Under ordinary conditions of storage and use, thesepreparations may contain a preservative to prevent the growth ofmicroorganisms.

Some embodiments include administration of a tablet that contains(S)-Bupropion in a form that provides sustained release of(S)-Bupropion. A sustained release dosage form containing (S)-Bupropionmay have a T_(max) of about 2-4 hours, 4-6 hours, or 6-8 hours. Whilethere are many ways that sustained release of bupropion may be achieved,in some embodiments, (S)-Bupropion or (R)-bupropion is combined with asustained release polymer, such as an acrylic acid or a methacrylic acidcopolymer or an ester thereof, e.g. a methyl methacrylate copolymer, anethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylicacid anhydride), a glycidyl methacrylate copolymers; a quaternizedaminoalkyl ester or an aminoalkyl amide of acrylic acid and/ormethacrylic acid, for example β-methacryloxyethyltrimethylammoniummethosulfate, β-acryloxypropyltrimethylammonium chloride, andtrimethylaminomethylmethacrylamide methosulfate, quaternizedvinyl-substituted nitrogen heterocycles such as methyl-vinyl pyridiniumsalts, vinyl esters of quaternized amino carboxylic acids,styryltrialkyl ammonium salts, benzyldimethylammoniumethylmethacrylatechloride, diethylmethylammoniumethyl-acrylate,diethylmethylammoniumethylmethacrylate methosulfate,N-trimethylammoniumpropylmethacrylamide chloride,N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride; acellulose derivative such as a carboxyalkylcellulose (e.g.carboxymethylcellulose), hydroxypropyl methylcellulose, etc. In someembodiments, the sustained release polymer is hydroxypropylmethylcellulose. For example, particles of (S)-Bupropion could beblended with microcrystalline cellulose and hydroxypropylmethylcellulose (e.g., METHOCEL®) to form a mixture of blended powders.

Examples of neurological disorders or central nervous system disordersthat may be treated by administering (S)-bupropion (includingadministering (S)-bupropion to achieve therapeutic plasma levels of oneof its metabolites, such as (R,R)-hydroxybupropion) include, but are notlimited to: affective disorders, psychiatric disorders, cerebralfunction disorders, movement disorders, dementias, motor neurondiseases, neurodegenerative diseases, seizure disorders, and headaches.

Affective disorders that may be treated by administering (S)-bupropion(including administering (S)-bupropion to achieve therapeutic plasmalevels of one of its metabolites, such as (R,R)-hydroxybupropion)include, but are not limited to, depression, major depression, treatmentresistant depression and treatment resistant bipolar depression, bipolardisorders including cyclothymia, seasonal affective disorder, mooddisorders, chronic depression (dysthymia), psychotic depression,postpartum depression, premenstrual dysphoric disorder (PMDD),situational depression, atypical depression, mania, anxiety disorders,attention deficit disorder (ADD), attention deficit disorder withhyperactivity (ADDH), and attention deficit/hyperactivity disorder(AD/HD), bipolar and manic conditions, obsessive-compulsive disorder,bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome,premenstrual syndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression may be manifested by depressive symptoms. These symptoms mayinclude psychological changes such as changes in mood, feelings ofintense sadness, despair, mental slowing, loss of concentration,pessimistic worry, agitation, anxiety, irritability, guilt, anger,feelings of worthlessness, reckless behavior, suicidal thoughts orattempts, and/or self-deprecation. Physical symptoms of depression mayinclude insomnia, anorexia, appetite loss, weight loss, weight gain,decreased energy and libido, fatigue, restlessness, aches, pains,headaches, cramps, digestive issues, and/or abnormal hormonal circadianrhythms.

Some patients, even after treatment with medications such asantidepressants, may have an inadequate or no response to the treatment.Treatment resistant depression (TRD), or treatment-refractorydepression, is a condition generally associated with patients who havefailed treatment with at least two antidepressants. Part of thediagnosis for TRD is for the patient to have had an inadequate responseto treatment with the antidepressants after an adequate dose andadequate course. TRD may be more difficult to treat due to thecomorbidity of other medical or psychological illnesses, such asdrug/alcohol abuse or eating disorders, or TRD being misdiagnosed. SomeTRD patients have had an inadequate response to 1, 2, 3, or moreadequate antidepressant treatment trials or have failed or had aninadequate response to 1, 2, 3, or more prior antidepressant treatments.In some embodiments, a patient being treated for treatment resistantdepression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, or more antidepressant therapies.

Measures of treatment effect that may be improved by administering(S)-bupropion (including administering (S)-bupropion to achievetherapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) include, but are not limited to:Montgomery-Asberg Depression Rating Scale (MADRS), Quality of LifeEnjoyment and Satisfaction Questionnaire Short Form, Range of ImpairedFunctioning Tool, Sheehan Disability Scale, Patient Rated Inventory ofSide Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS),Quick Inventory of Depressive Symptomatology, Self-Report (QID(S)-SR),Clinical Global Impression (CGI) scale, Massachusetts General HospitalCognitive and Physical Functioning Questionnaire (CPFQ), 17-itemHamilton Rating Scale for Depression (HAM-D17), Massachusetts GeneralHospital Antidepressant Treatment Response Questionnaire (MGH ATRQ),16-item Quick Inventory of Depressive Symptomatology—Self Report(QID(S)-SR16), Sheehan Disability Scale (SDS), Clinical GlobalImpression of Severity of Illness (CGI-S), Clinical Global Impression ofChange (CGI-C), EuroQOL 5 Dimension 5 Level (EQ-5D-5L), Patient GlobalImpression of Change (PGIC), 7-item Generalized Anxiety Disorder(GAD-7), Clinical Global Impressions-Improvement (CGI-I). SheehanDisability Scale (SDS). 16-item Quick Inventory of DepressiveSymptomatology—Self Report (QID(S)-SR16), Hamilton Anxiety Scale(HAM-A), Massachusetts General Hospital Cognitive and PhysicalFunctioning Questionnaire (CPFQ), CPFQ—Cognitive subscales (Items 4 to7), Brief Psychiatric Rating Scale (BPRS), etc.; Digit SymbolSubstitution Test (DSST), Rey Auditory Verbal Learning Task (RAVLT),Trail Making Test (TMT), Stroop Colour Naming Test (STROOP), SimpleReaction Time (SRT), Choice Reaction Time (CRT), etc.

Patients who may benefit from the treatments described herein includepediatric patients, such as patients under about 18 years of age, about0-5 years of age, about 5-10 years of age, about 10-12 years of age, orabout 12-18 years of age, adult patients, such as patients having an ageof about 18-65 years; about 18-30 years; about 30-50 years; about 50-65years, and elderly patients, such as patients over 65 years of age;about 65-75 years of age; about 75-90 years of age; or over 90 years ofage.

Treatment of TRD by administering (S)-bupropion (including administering(S)-bupropion to achieve therapeutic plasma levels of one of itsmetabolites, such as (R,R)-hydroxybupropion) may result in a reductionof depressive symptoms of at least about 5%, at least about 10%, atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, up to about 100%, or any other reduction percentage ina range bounded by any of these values.

Psychiatric disorders that may be treated by administering (S)-bupropion(including administering (S)-bupropion to achieve therapeutic plasmalevels of one of its metabolites, such as (R,R)-hydroxybupropion)include, but are not limited to, anxiety disorders, such as phobias,generalized anxiety disorder, social anxiety disorder, panic disorder,agoraphobia, obsessive-compulsive disorder, and post-traumatic stressdisorder (PTSD); mania, manic depressive illness, hypomania, unipolardepression, depression, stress disorders, somatoform disorders,personality disorders, psychosis, schizophrenia, delusional disorder,schizoaffective disorder, schizotypy, aggression, aggression inAlzheimer's disease, agitation, and agitation in Alzheimer's disease.

Agitation associated with Alzheimer's disease occurs as the diseaseprogresses. Agitation may present itself as inappropriate verbal,emotional, and/or physical behaviors. Inappropriate behaviors mayinclude, but are not limited to, incoherent babbling, inappropriateemotional response, demands for attention, threats, irritability,frustration, screaming, repetitive questions, mood swings, cursing,abusive language, physical outbursts, emotional distress, restlessness,shredding, sleeping disturbances, delusions, hallucinations, pacing,wandering, searching, rummaging, repetitive body motions, hoarding,shadowing, hitting, scratching, biting, combativeness, hyperactivity,and/or kicking.

In some embodiments, treatment of agitation associated with Alzheimer'sdisease by administering (S)-bupropion (including administering(S)-bupropion to achieve therapeutic plasma levels of one of itsmetabolites, such as (R,R)-hydroxybupropion) may result in a reductionof agitation-related symptoms of at least about 5%, at least about 10%,at least about 20%, at least about 30%, at least about 40%, at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, and/or up to about 100%.

Measures of treatment effect of agitation that may be improved byadministering (S)-bupropion (including administering (S)-bupropion toachieve therapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) include, but are not limited to,Neuropsychiatric Inventory-Clinician (NPI-C) rating scale, overall andall domains; Neuropsychiatric Inventory-Clinician (NPI-C) rating scaleAgitation domain; Cohen-Mansfield Agitation Inventory (CMAI); CornellScale for Depression in Dementia (CSDD); Neuropsychiatric Inventory (NPIAgitation/Aggression Domain); Cocomitant Medications (Frequency of usingconcomitant medications); Alzheimer's Disease CooperativeStudy—Activities of Daily Living Inventory (ADC(S)-ADL);Neuropsychiatric Inventory (NPI) Individual Domains and NPI Total Scores(range 0-144), including NPI-C Apathy domain, NPI Agitation/AggressionCaregiver Distress, Modified Alzheimer's Disease CooperativeStudy-Clinical Global Impression of Change Agitation (mADC(S)-CGICAgitation), Patient Global Impression of Change (PGIC) (rated bycaregiver), Dementia Quality of Life (DEMQOL), Quality ofLife-Alzheimer's disease measure (QoL-AD), Zarit Burden Scale, ResourceUtilization in Dementia (RUD), Alzheimer's Disease AssessmentScale-Cognitive Subscale (ADA(S)-Cog), Mini-mental State Examination(MMSE), Caregiver Strain Index (CSI), Individual Domain of theNeuropsychiatric Inventory (NPI), Total Neuropsychiatric Inventory (NPI)Score, Neuropsychiatric Inventory (Agitation/Aggression Domain of NPI),Neuropsychiatric Inventory (Caregiver Distress for NPI Domains), etc.

Substance addiction abuse that may be treated by administering(S)-bupropion (including administering (S)-bupropion to achievetherapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) includes, but is not limited to, drugdependence, addiction to cocaine, psychostimulants (e.g., crack,cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic andhypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens,phencyclidine, volatile solvents, and volatile nitrites. Nicotineaddiction includes nicotine addiction of all known forms, such assmoking cigarettes, cigars and/or pipes, electronic cigarettes, andaddiction to chewing tobacco.

Cerebral function disorders that may be treated by administering(S)-bupropion (including administering (S)-bupropion to achievetherapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) include, but are not limited to, disordersinvolving intellectual deficits such as senile dementia, Alzheimer'stype dementia, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome,autism, hyperkinetic syndrome, and schizophrenia. Cerebral functiondisorders also include disorders caused by cerebrovascular diseasesincluding, but not limited to, stroke, cerebral infarction, cerebralbleeding, cerebral arteriosclerosis, cerebral venous thrombosis, headinjuries, and the like where symptoms include disturbance ofconsciousness, senile dementia, coma, lowering of attention, and speechdisorders.

Movement disorders that may be treated by administering (S)-bupropion(including administering (S)-bupropion to achieve therapeutic plasmalevels of one of its metabolites, such as (R,R)-hydroxybupropion)include, but are not limited to, akathisia, akinesia, associatedmovements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia,cerebral palsy, chorea, Huntington's disease, rheumatic chorea,Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia,blepharospasm, spasmodic torticollis, dopamine-responsive dystonia,Parkinson's disease, restless legs syndrome (RLS), tremor, essentialtremor, and Tourette's syndrome, and Wilson's disease.

Dementias that may be treated by administering (S)-bupropion (includingadministering (S)-bupropion to achieve therapeutic plasma levels of oneof its metabolites, such as (R,R)-hydroxybupropion) include, but are notlimited to, Alzheimer's disease, Parkinson's disease, vascular dementia,dementia with Lewy bodies, mixed dementia, fronto-temporal dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington'sdisease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by administering (S)-bupropion(including administering (S)-bupropion to achieve therapeutic plasmalevels of one of its metabolites, such as (R,R)-hydroxybupropion)include, but are not limited to, amyotrophic lateral sclerosis (ALS),progressive bulbar palsy, primary lateral sclerosis (PLS), progressivemuscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy(SMA), spinal motor atrophies, Tay-Sach's disease, Sandoff disease, andhereditary spastic paraplegia.

Neurodegenerative diseases that may be treated by administering(S)-bupropion (including administering (S)-bupropion to achievetherapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) include, but are not limited to Alzheimer'sdisease, prion-related diseases, cerebellar ataxia, spinocerebellarataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy,Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson'sdisease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease),multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome,corticobasal degeneration, progressive supranuclear palsy, Wilson'sdisease, Menkes disease, adrenoleukodystrophy, cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT),familial spastic paraparesis, neurofibromatosis, olivopontine cerebellaratrophy or degeneration, striatonigral degeneration, Guillain-Barrésyndrome, and spastic paraplegia.

Seizure disorders that may be treated by administering (S)-bupropion(including administering (S)-bupropion to achieve therapeutic plasmalevels of one of its metabolites, such as (R,R)-hydroxybupropion)include, but are not limited to, epileptic seizures, nonepilepticseizures, epilepsy, febrile seizures; partial seizures including, butnot limited to, simple partial seizures, Jacksonian seizures, complexpartial seizures, and epilepsia partialis continua; generalized seizuresincluding, but not limited to, generalized tonic-clonic seizures,absence seizures, atonic seizures, myoclonic seizures, juvenilemyoclonic seizures, and infantile spasms; and status epilepticus.

Types of headaches that may be treated administering (S)-bupropion(including administering (S)-bupropion to achieve therapeutic plasmalevels of one of its metabolites, such as (R,R)-hydroxybupropion)include, but are not limited to, migraine, tension, and clusterheadaches.

Other neurological disorders that may be treated by administering(S)-bupropion (including administering (S)-bupropion to achievetherapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) include, Rett Syndrome, autism, tinnitus,disturbances of consciousness disorders, sexual dysfunction, intractablecoughing, narcolepsy, cataplexy; voice disorders due to uncontrolledlaryngeal muscle spasms, including, but not limited to, abductorspasmodic dysphonia, adductor spasmodic dysphonia, muscular tensiondysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-inducedneurotoxicity, such as methotrexate neurotoxicity; incontinenceincluding, but not limited, stress urinary incontinence, urge urinaryincontinence, and fecal incontinence; and erectile dysfunction.

In some embodiments, administering (S)-bupropion (includingadministering (S)-bupropion to achieve therapeutic plasma levels of oneof its metabolites, such as (R,R)-hydroxybupropion) may be useful totreat pain, joint pain, pain associated with sickle cell disease,pseudobulbar affect, depression (including treatment resistantdepression), disorders related to memory and cognition, schizophrenia,Parkinson's disease, amyotrophic lateral sclerosis (ALS), seizures,cough (including chronic cough), etc.

In some embodiments, refractory depression may be treated byadministering (S)-bupropion (including administering (S)-bupropion toachieve therapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion).

(S)-bupropion may also be used (either by direct action of(S)-bupropion, or by administration of (S)-bupropion to achievetherapeutic plasma levels of one of its metabolites, such as(R,R)-hydroxybupropion) to treat, or provide relief to, any type of painincluding, but not limited to, musculoskeletal pain, neuropathic pain,cancer-related pain, acute pain, nociceptive pain, inflammatory pain,arthritis pain, complex regional pain syndrome, etc.

In some embodiments, (S)-bupropion may be administered (either for itsdirect action, or to achieve therapeutic plasma levels of one of itsmetabolites, such as (R,R)-hydroxybupropion) to relieve neuropathicpain.

Examples of neuropathic pain include diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, central pain, etc. Other causes of neuropathic paininclude cancer-related pain, lumbar nerve root compression, spinal cordinjury, post-stroke pain, central multiple sclerosis pain,HIV-associated neuropathy, and radio- or chemo-therapy associatedneuropathy, etc.

In some embodiments, (S)-bupropion may be administered (either for itsdirect action, or to achieve therapeutic plasma levels of one of itsmetabolites, such as (R,R)-hydroxybupropion) to relieve fibromyalgia.

Adverse events associated with bupropion that may be avoided or reducedby a method described herein include a central nervous system adverseevent, a gastrointestinal event, or another type of adverse eventassociated with any of these compounds. Central nervous system (CNS)adverse events include, but are not limited to, nervousness, dizziness,sleeplessness, light-headedness, tremor, hallucinations, convulsions,CNS depression, fear, anxiety, headache, increased irritability orexcitement, tinnitus, drowsiness, dizziness, sedation, somnolence,confusion, disorientation, lassitude, incoordination, fatigue, euphoria,nervousness, insomnia, sleeping disturbances, convulsive seizures,excitation, catatonic-like states, hysteria, hallucinations, delusions,paranoia, headaches and/or migraine, and extrapyramidal symptoms such asoculogyric crisis, torticollis, hyperexcitability, increased muscletone, ataxia, and/or tongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea,vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominaldistension, flatulence, peptic ulcers with bleeding, loose stools,constipation, stomach pain, heartburn, gas, loss of appetite, feeling offullness in stomach, indigestion, bloating, hyperacidity, dry mouth,gastrointestinal disturbances, and gastric pain.

Other adverse events that may be reduced or avoided by a methoddescribed herein include abnormal sensation of rotation and movement,agitation, arm weakness, bloating, blurred vision, burning sensation inthe eyes, buzzing sound in ear, changes in vital signs (including, butnot limited to, heart rate, respiratory rate, body temperature, bloodpressure), cold sensation, constipation, difficulty concentrating,difficulty sleeping, difficulty in falling asleep, difficulty urinating,difficulty with bowel movement, discomfort in the ear, discomfort in theeye, discomfort in the stomach, dizziness, dry lips, dry mouth, drythroat, dysmenorrhea, fatigue, feeling feverish, feeling heavy headed,feeling more agitated than usual, feeling more tired than usual, feelingtired, hand tremors, hand weakness, headache, heartburn, hot flashes,increased blood pressure, increased skin sensitivity, increased skinsensitivity at head and face, involuntary muscle contraction,involuntary muscle contractions at all over the body, knee pain, legweakness, lightheadedness, loose stool, loss of appetite, low back pain,menstrual disorder, metallic taste, more saliva than usual, mucosaldryness, nasal congestion, nausea, runny nose, sensation of lightpressure sensation in the eyes, shivers when stretching or yawning, skinsensitivity, skin sensitivity in arm, face, and/or head, sleepdifficulties, soft stools, stomach ache, stomach discomfort, sweatyhands and/or feet, throat irritation, throat pain, tinnitus, tremors,and/or weakness. Any of these side effects may also be referred to, orgrouped, according to a corresponding, equivalent, or otherwise relevantterm found in the Medical Dictionary for Regulatory Activities (MedRA).

The following embodiments are contemplated:

Embodiment 1

A method of providing (R)-bupropion and (S)-bupropion to the plasma,comprising:

selecting a human being in need of the pharmacokinetic profile providedby orally administering a reference dosage form containing a firstamount of racemic bupropion at a first dosing frequency; and

orally administering a dosage form containing a second amount of(S)-bupropion that is at least 95% enantiomerically pure at the firstdosing frequency to achieve the same pharmacokinetic profile that wouldbe achieved by administering the reference dosage form at the firstdosing frequency;

wherein the first dosing frequency is once daily or twice daily; and

wherein the second amount is about 40% to about 60% of the first amount.

Embodiment 2

A method of treating a condition that is treatable with racemicbupropion, comprising:

selecting a human patient having the condition that is treatable byorally administering a reference dosage form containing a first amountof racemic bupropion at a first dosing frequency; and

orally administering a dosage form containing a second amount of(S)-bupropion that is at least 95% enantiomerically pure at the firstdosing frequency to achieve the same therapeutic effect that would beachieved by administering the reference dosage form at the first dosingfrequency;

wherein the first dosing frequency is once daily or twice daily; and

wherein the second amount is about 40% to about 60% of the first amount.

Embodiment 3

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being has a condition that is treatable with(S)-bupropion, wherein the amount of (S)-bupropion administered isselected to be about 20% to about 70% by weight of the amount of racemicbupropion that would be administered to treat the same human being forthe same condition.

Embodiment 4

A method of providing therapeutically effective plasma levels of(R,R)-hydroxybupropion comprising orally administering, one or two timesper day, a dosage form containing (S)-bupropion that is at least 95%enantiomerically pure, to a human being in need of treatment with(R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97%of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropionpresent in the plasma of the human being, and wherein the methodachieves a C_(max) of (R,R)-hydroxybupropion that is at least about 500ng/mL in the human being.

Embodiment 5

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure to the human being, wherein the human being is inneed of treatment with (S)-bupropion, wherein the (S)-bupropion is thesole active agent used to treat the human being.

Embodiment 6

A method of treating a human being comprising orally administering adosage form containing about 50 mg to about 100 mg of (S)-bupropion thatis at least 95% enantiomerically pure, one or two times per day, to thehuman being, wherein the human being is in need of treatment with(S)-bupropion.

Embodiment 7

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves a C_(max) of (S)-bupropion that is at leastabout 60 ng/mL.

Embodiment 8

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein (R,R)-hydroxybupropion is at least 97% of the total of amount of(R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasmaof the human being.

Embodiment 9

A method of providing therapeutically effective plasma levels of(R,R)-hydroxybupropion comprising orally administering, one or two timesper day, a dosage form containing (S)-bupropion that is at least 95%enantiomerically pure, to a human being in need of treatment with(R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97%of the total of amount of (R,R)-hydroxybupropion and(S,S)-hydroxybupropion present in the plasma of the human being.

Embodiment 10

A method of providing therapeutically effective plasma levels of(R,R)-hydroxybupropion comprising orally administering, one or two timesper day, a dosage form containing (S)-bupropion that is at least 95%enantiomerically pure, to a human being in need of treatment with(R,R)-hydroxybupropion, wherein the method achieves a C_(max) of(R,R)-hydroxybupropion that is at least about 500 ng/mL in the humanbeing.

Embodiment 11

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves a C_(max) of (S)-bupropion that is at leastabout 70 ng/mL.

Embodiment 12

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves an AUC₀₋₁₂ of (S)-bupropion that is at leastabout 600 ng·h/mL.

Embodiment 13

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves a C_(max) of (R,R)-hydroxybupropion that isat least about 800 ng/mL.

Embodiment 14

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves an AUC₀₋₁₂ of (R,R)-hydroxybupropion that isat least about 8,000 ng·h/mL.

Embodiment 15

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves a C_(max) of erythrohydroxybupropion that isat least about 90 ng/mL.

Embodiment 16

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves an AUC₀₋₁₂ of erythrohydroxybupropion thatis at least about 1,000 ng·h/mL.

Embodiment 17

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being,wherein the human being is in need of treatment with (S)-bupropion,wherein the method achieves a C_(max) of threohydroxybupropion that isat least about 450 ng/mL.

Embodiment 18

A method of treating a human being comprising orally administering adosage form containing (S)-bupropion that is at least 95%enantiomerically pure, one or two times per day, to the human being inneed of treatment with (S)-bupropion, wherein the method achieves anAUC₀₋₁₂ of threohydroxybupropion that is at least about 5,000 ng·h/mL.

Embodiment 19

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, or 18, wherein the human being is in need of treatment with(S)-bupropion.

Embodiment 20

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, or 19, wherein the method achieves a C_(max) of(S)-bupropion that is at least about 60 ng/mL.

Embodiment 21

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20, wherein the method is effective in increasingthe C_(max) of (S)-bupropion at least 5-fold as compared to the C_(max)of (R)-bupropion that results from administering the same amount of(R)-bupropion to the human being.

Embodiment 22

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, or 21, wherein the method achieves a C_(max) of(R,R)-hydroxybupropion that is at least about 500 ng/mL in the humanbeing.

Embodiment 23

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, or 22, wherein the method is effective inincreasing the C_(min) of (R,R)-hydroxybupropion at least 3-fold ascompared to the C_(min) of (R,R)-hydroxybupropion that results fromadministering the same amount of (R)-bupropion to the human being.

Embodiment 24

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the dosage form isadministered once daily.

Embodiment 25

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein the dosage form isadministered twice daily.

Embodiment 26

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein(R,R)-hydroxybupropion is at least 97% of the total of amount of(R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasmaof the human being.

Embodiment 27

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, which is effective inproviding therapeutically effective plasma levels of(R,R)-hydroxybupropion.

Embodiment 28

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, which iseffective in providing therapeutically effective plasma levels of(S)-bupropion.

Embodiment 29

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein thehuman being is in need of treatment with (R,R)-hydroxybupropion.

Embodiment 30

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, whereinthe method achieves a C_(max) of (R,R)-hydroxybupropion that is at leastabout 500 ng/mL in the human being.

Embodiment 31

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30,wherein the dosage form is administered for at least 8 consecutive days.

Embodiment 32

The method of embodiment 31, wherein the dosage form is administered forat least 14 consecutive days.

Embodiment 33

The method of embodiment 31, wherein the dosage form is administered forat least 21 consecutive days.

Embodiment 34

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,or 33, wherein the dosage form contains about 60 mg to about 90 mg of(S)-bupropion.

Embodiment 35

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, or 34, wherein the dosage form is administered once daily for 1 to 3consecutive days, then the dosage form is administered twice a day forat least the following 4 to 7 consecutive days, so that the dosage formis administered once daily or twice daily for a total of at least 8consecutive days.

Embodiment 36

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, or 35, wherein the dosage form is administered once daily for 1to 7 consecutive days, then the dosage form is administered twice a dayfor at least the following 7 consecutive days, so that the dosage formis administered once daily or twice daily for a total of at least 8consecutive days.

Embodiment 37

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, or 36, wherein the dosage form contains about 70 mg to about80 mg of the (S)-bupropion.

Embodiment 38

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, or 37, wherein the method achieves a C_(max) of(S)-bupropion in the human being that is at least about 70 ng/mL.

Embodiment 39

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, or 38, wherein the method achieves an AUC₀₋₁₂ of(S)-bupropion in the human being that is at least about 400 ng·hr/mL.

Embodiment 40

The method of embodiment 39, wherein the method achieves an AUC₀₋₁₂ of(S)-bupropion in the human being that is about 500 ng·hr/mL to about 900ng·hr/mL.

Embodiment 41

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, or 40, wherein the dosage form providessustained release of the (S)-bupropion.

Embodiment 42

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, or 41, wherein the dosage form containsabout 70 mg to about 80 mg of the (S)-bupropion.

Embodiment 43

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein the method achieves aC_(max) of (R,R)-hydroxybupropion in the human being that is at leastabout 600 ng/mL.

Embodiment 44

The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44, wherein the methodachieves an AUC₀₋₁₂ of (R,R)-hydroxybupropion in the human being that isat least about 7000 ng·hr/mL.

Embodiment 45

The method of embodiment 44, wherein the method achieves an AUC₀₋₁₂ of(R,R)-hydroxybupropion in the human being that is at least about 8000ng·hr/mL.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, AUC values, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein.

Accordingly, the claims include all modifications and equivalents of thesubject matter recited in the claims as permitted by applicable law.Moreover, any combination of the above-described elements in allpossible variations thereof is contemplated unless otherwise indicatedherein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

What is claimed is:
 1. A method of treating attentiondeficit/hyperactivity disorder (AD/HD) comprising orally administeringan (S)-bupropion that is at least 95% enantiomerically pure to a humanbeing in need thereof, wherein the (S)-bupropion is notdeuterium-enriched, wherein about 20 mg to about 100 mg of the(S)-bupropion is orally administered once daily and is therapeuticallyeffective for treating AD/HD, wherein the (S)-bupropion that is at least95% enantiomerically pure is orally administered in a dosage form thatis free of any active pharmaceutical ingredients other than the(S)-bupropion that is at least 95% enantiomerically pure and theaccompanying 5% or less (R)-bupropion.
 2. The method of claim 1, whereinthe human being has an age of about 18 years or less.
 3. The method ofclaim 1, wherein the dosage form contains a binder.
 4. The method ofclaim 1, wherein the dosage form contains an excipient.
 5. The method ofclaim 1, wherein the dosage form contains a disintegrating agent.
 6. Themethod of claim 1, wherein the dosage form contains a lubricant.
 7. Themethod of claim 1, wherein the method achieves a C_(max) of(S)-bupropion in the human being that is at least about 60 ng/mL.
 8. Themethod of claim 1, wherein the method is effective in achieving aC_(max) of (S)-bupropion that is at least 5-fold greater than theC_(max) of (R)-bupropion that results from orally administering the sameamount of (R)-bupropion to the human being.
 9. The method of claim 1,wherein the method achieves a C_(max) of (R,R)-hydroxybupropion that isat least about 500 ng/mL in the human being.
 10. The method of claim 1,wherein the method is effective in achieving a C_(min) of(R,R)-hydroxybupropion that is at least 3-fold greater than the C_(min)of (R,R)-hydroxybupropion that results from orally administering thesame amount of (R)-bupropion to the human being.
 11. The method of claim1, wherein orally administering the (S)-bupropion results in(R,R)-hydroxybupropion that is at least 97% of the total amount ofhydroxybupropion present in the plasma of the human being.
 12. Themethod of claim 1, wherein the (S)-bupropion is orally administered forat least 8 consecutive days.
 13. The method of claim 1, wherein the(S)-bupropion is orally administered for at least 14 consecutive days.14. The method of claim 1, wherein the (S)-bupropion is orallyadministered for at least 21 consecutive days.
 15. The method of claim1, wherein the dosage form provides sustained release of (S)-bupropion.16. The method of claim 1, wherein the method achieves a C_(max) of(R,R)-hydroxybupropion in the human being that is at least about 600ng/mL.
 17. The method of claim 1, wherein the dosage form is in a formof tablet, capsule, or syrup.
 18. The method of claim 1, wherein thedosage form is orally administered to the human being under fastingconditions.
 19. The method of claim 1, wherein the (S)-bupropion is atleast 97% enantiomerically pure.
 20. The method of claim 1, wherein the(S)-bupropion is at least 99% enantiomerically pure.
 21. The method ofclaim 1, wherein the (S)-bupropion is in a salt form.
 22. The method ofclaim 1, wherein the (S)-bupropion is in the free base form.